This application focuses on intervention during early withdrawal from cocaine self-administration to suppress persistent cocaine-seeking and underlying neuroadaptations. We have based this approach on findings in which brain-derived neurotrophic factor (BDNF) infused into the dorsomedial prefrontal cortex (dmPFC) of rats immediately after the last cocaine self-administration session suppresses cocaine-seeking in an ERK MAP kinase-dependent manner. BDNF reverses cocaine-induced dephosphorylation of ERK and CREB in the dmPFC within 2 hr after the end of cocaine self-administration. If BDNF administration is delayed after the end of self-administration, it has no effect on cue-induced cocaine-seeking. Thus, the first few hr after the end of repeated cocaine exposure appear to be critical for BDNF's actions. We hypothesize that this timing is linked to the transient nature of ERK and CREB dephosphorylation (or shutoff') that recovers by 22 hr after the end of cocaine self-administration. Further, preliminary data presented in this proposal implicate the striatal-enriched tyrosine phosphatase (STEP) in cocaine SA-induced ERK dephosphorylation in the dmPFC. Based on this foundation, we will investigate the role of synaptic activity (Aim 1 and 2) and kinase- phosphatase balance (Aims 3 and 4) in the ability of intra-PFC BDNF to normalize ERK phosphorylation in dmPFC during early withdrawal and suppress cocaine-seeking in rats with a cocaine SA history.